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From a public health perspective, new antibacterial agents should be evaluated and approved for use before widespread resistance to existing agents emerges. However, for multidrug-resistant pathogens, demonstration of superior efficacy of a new agent over a current standard-of-care agent is routinely feasible only when epidemic spread of these dangerous organisms has already occurred. One solution to enable proactive drug development is to evaluate new antibiotics with improved in vitro activity against MDR pathogens using recently updated guidelines for active control, noninferiority trials of selected severe infections caused by more susceptible pathogens. Such trials are feasible because they enroll patients with infections due to pathogens with a "usual drug resistance" phenotype that will be responsive to widely registered standard-of-care comparator antibiotics. Such anticipatory drug development has constructively reshaped the antibiotic pipeline and offers the best chance of making safe and efficacious antibiotics available to the public ahead of epidemic resistance., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Traditionally, medical and biostatistical experts have played a central role in ensuring validity of pharmaceutical testing. The science of pharmacometrics provides powerful approaches for supporting important drug development and regulatory decisions. Numerous case studies published by academic, industry, and US Food and Drug Administration scientists attest to the significant contribution of pharmacometrics to decision making. The economic and public health benefits of applying this discipline to clinical trials far outweigh the cost associated with its implementation. The purpose of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) Task Force is to build on the momentum and accelerate dissemination of its impact and adoption into drug development. We describe briefly the contributions of pharmacometrics and the specific goals of the Task Force.

Between 1985 and 1991, 39,000 cases of tuberculosis occurred in excess of those expected based on previous trends. Immigration from high-prevalence countries, coinfection with human immunodeficiency virus (HIV), and outbreaks in congregative facilities are most responsible for the increase. Coincident with the increase in tuberculosis, outbreaks of multidrug resistant (MDR) tuberculosis have occurred. Clinical and epidemiologic data support nosocomial transmission. MDR tuberculosis occurred late in the course of HIV infection and was refractory to treatment. Compounding the problems of rising incidence and increasing resistance was the sudden recognition of shortages of antituberculous drugs. The problems currently posed by tuberculosis require new approaches to diagnosis and rapid sensitivity testing as well as assuring an adequate supply of licensed drugs and development of new drugs. A number of steps have been taken by governmental agencies to assure that the challenge is met.

Note from Dr. Merle A. Sande--The role of Mycobacterium avium as a pathogen in the human immunodeficiency virus-infected population has been confusing and controversial to clinicians who care for AIDS patients. The organism is commonly isolated from respiratory secretions of patients with other infections and often seems part of the resident flora; even when isolated from the bone marrow or bloodstream, its impact on the course of AIDS and contribution to systemic diseases are unknown. However, an increasing subset of patients without other documented opportunistic infections or malignancies has symptoms that respond to therapy directed against M. avium. Studies are in progress to evaluate chemotherapeutic agents. Accordingly, the subject is here reviewed and guidelines offered to infectious disease clinicians by one with a long-standing interest in mycobacterial disease who has made numerous contributions to the field.

The pharmacology of cefamandole in seven patients with stable renal insufficiency and in eight patients undergoing hemodialysis was determined. All patients had creatinine clearances less than 5 ml/min. The half-life of cefamandole in those patients with stable chronic renal failure was 7.7 +/- 2.2 h. The mean venous level 1 h after intravenous injection of a 1-g dose was 85.3 +/- 32.0 mug/ml. The mean venous half-life of cefamandole during hemodialysis was 6.1 h. The venous serum level after 5.5 of hemodialysis was 50.4 +/- 20.8 mug/ml. The mean coefficient of extraction was 0.155, and the mean clearance was 34.7 ml/min. The time interval between doses of cefamandole administered intravenously should be lengthened to 24 h in the presence of stable renal failure. No major change in dosage schedule is necessary for patients undergoing dialysis.

Tuberculosis, once considered a problem solved, is now dramatically on the rise. New approaches to chemotherapy will hopefully help to control this again serious problem. This article reviews the current status of tuberculosis chemotherapy, including the management of drug-resistant cases.

Forty-four patients with serious bacterial infections were treated with cefamandole in a dose 1--2 g every four to six hours. Thirty-two patients were cured and six were markedly improved. Three of six failures were due to superinfection with cephalothin-resistant microorganisms. The over-all bacteriologic response was 80%. In 12 of 13 patients with bacteremia the blood was sterilized. Ten of 14 patients with gram-negative bacillary infections responded to treatment. Six of these were due to cephalothin-resistant microorganisms, three of which responded. Fifteen patients who were treated had a history of penicillin allergy. There were no serious reactions although skin rash did develop. Phlebitis was uncommon.